2. Academic Validation
  3. Promiscuous targeting of bromodomains by bromosporine identifies BET proteins as master regulators of primary transcription response in leukemia

Promiscuous targeting of bromodomains by bromosporine identifies BET proteins as master regulators of primary transcription response in leukemia

  • Sci Adv. 2016 Oct 12;2(10):e1600760. doi: 10.1126/sciadv.1600760.
Sarah Picaud 1,  Katharina Leonards 2,  Jean-Philippe Lambert 3,  Oliver Dovey 4,  Christopher Wells 1,  Oleg Fedorov 5,  Octovia Monteiro 5,  Takao Fujisawa 6,  Chen-Yi Wang 6,  Hannah Lingard 1,  Cynthia Tallant 5,  Nikzad Nikbin 7,  Lucie Guetzoyan 7,  Richard Ingham 7,  Steven V Ley 7,  Paul Brennan 8,  Susanne Muller 5,  Anastasia Samsonova 9,  Anne-Claude Gingras 10,  Juerg Schwaller 2,  George Vassiliou 11,  Stefan Knapp 12,  Panagis Filippakopoulos 13
Affiliations

Affiliations

  • 1 Structural Genomics Consortium, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, U.K.
  • 2 Laboratory of Childhood Leukemia, Department of Biomedicine, University of Basel and Basel University Children's Hospital, Hebelstrasse 20, CH-4031 Basel, Switzerland.
  • 3 Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, Canada.
  • 4 Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, U.K.
  • 5 Structural Genomics Consortium, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, U.K.; Target Discovery Institute, University of Oxford, Oxford OX3 7FZ, U.K.
  • 6 Ludwig Institute for Cancer Research, University of Oxford, Oxford OX3 7DQ, U.K.
  • 7 Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, U.K.
  • 8 Structural Genomics Consortium, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, U.K.; Target Discovery Institute, University of Oxford, Oxford OX3 7FZ, U.K.; Alzheimer's Research UK Oxford, Nuffield Department of Medicine Research Building, University of Oxford, Oxford OX3 7FZ, U.K.
  • 9 Department of Oncology, CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford OX3 7DQ, U.K.
  • 10 Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, Canada.; Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
  • 11 Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, U.K.; Department of Haematology, Cambridge University Hospitals NHS Trust, Cambridge CB2 0QQ, U.K.; Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0XY, U.K.
  • 12 Structural Genomics Consortium, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, U.K.; Target Discovery Institute, University of Oxford, Oxford OX3 7FZ, U.K.; Institute for Pharmaceutical Chemistry and Buchmann Institute for Life Sciences, Goethe University, Max-von Laue Str. 9, 60438 Frankfurt am Main, Germany.
  • 13 Structural Genomics Consortium, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, U.K.; Ludwig Institute for Cancer Research, University of Oxford, Oxford OX3 7DQ, U.K.
PMID: 27757418 DOI: 10.1126/sciadv.1600760
Abstract

Bromodomains (BRDs) have emerged as compelling targets for Cancer therapy. The development of selective and potent BET (bromo and extra-terminal) inhibitors and their significant activity in diverse tumor models have rapidly translated into clinical studies and have motivated drug development efforts targeting non-BET BRDs. However, the complex multidomain/subunit architecture of BRD protein complexes complicates predictions of the consequences of their pharmacological targeting. To address this issue, we developed a promiscuous Brd Inhibitor [bromosporine (BSP)] that broadly targets BRDs (including BETs) with nanomolar affinity, creating a tool for the identification of cellular processes and diseases where BRDs have a regulatory function. As a proof of principle, we studied the effects of BSP on leukemic cell lines known to be sensitive to BET inhibition and found, as expected, strong antiproliferative activity. Comparison of the modulation of transcriptional profiles by BSP after a short exposure to the inhibitor resulted in a BET inhibitor signature but no significant additional changes in transcription that could account for inhibition of other BRDs. Thus, nonselective targeting of BRDs identified BETs, but not other BRDs, as master regulators of context-dependent primary transcription response.

Keywords

BET; Bromodomains; epigenetics; inhibition; leukemias.

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